tbuckley/cabot-search huggingface dataset:
Recommendations on the use and reporting of race, ethnicity, and ancestry in genetic research: Experiences from the NHLBI TOPMed program
Authors: Alyna T. Khan, Stephanie M. Gogarten, Caitlin P. McHugh, Adrienne M. Stilp, Tamar Sofer, Michael L. Bowers, Quenna Wong, L. Adrienne Cupples, Bertha Hidalgo, Andrew D. Johnson, Merry-Lynn N. McDonald, Stephen T. McGarvey, Matthew R.G. Taylor, Stephanie M. Fullerton, Matthew P. Conomos, Sarah C. Nelson
Journal: Cell Genomics (2022)

How race, ethnicity, and ancestry are used in genomic research has wide-ranging implications for how research is translated into clinical care and incorporated into public understanding. Correlation between race and genetic ancestry contributes to unresolved complexity for the scientific community, as illustrated by heterogeneous definitions and applications of these variables. Here, we offer commentary and recommendations on the use of race, ethnicity, and ancestry across the arc of genetic research, including data harmonization, analysis, and reporting. While informed by our experiences as researchers affiliated with the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, these recommendations are applicable to basic and translational genomic research in diverse populations with genome-wide data. Moving forward, considerable collaborative effort will be required to ensure that race, ethnicity, and ancestry are described and used appropriately to generate scientific knowledge that yields broad and equitable benefit.
Single-cell RNA sequencing depicts the local cell landscape in thyroid-associated ophthalmopathy
Authors: Zhaohuai Li, Mei Wang, Jia Tan, Lei Zhu, Peng Zeng, Xiaozhen Chen, Lihui Xie, Runping Duan, Binyao Chen, Tianyu Tao, Rong Wang, Xianggui Wang, Wenru Su
Journal: Cell Reports Medicine (2022)

There is a specific reactivity and characteristic remodeling of the periocular tissue in thyroid-associated ophthalmopathy (TAO). However, local cell changes responsible for these pathological processes have not been sufficiently identified. Here, single-cell RNA sequencing is performed to characterize the transcriptional changes of cellular components in the orbital connective tissue in individuals with TAO. Our study shows that lipofibroblasts with RASD1 expression are highly involved in inflammation and adipogenesis during TAO. ACKR1+ endothelial cells and adipose tissue macrophages may engage in TAO pathogenesis. We find CD8+CD57+ cytotoxic T lymphocytes with the terminal differentiation phenotype to be another source of interferon-γ, a molecule actively engaging in TAO pathogenesis. Cell-cell communication analysis reveals increased activity of CXCL8/ACKR1 and TNFSF4/TNFRSF4 interactions in TAO. This study provides a comprehensive local cell landscape of TAO and may be valuable for future therapy investigation.
Microbial short-chain fatty acids: a strategy to tune adoptive T cell therapy
Authors: Priya Rangan, Anna Mondino
Journal: Journal for ImmunoTherapy of Cancer (2022)

The gut microbiota and its metabolites have been shown to play a pivotal role in the regulation of metabolic, endocrine and immune functions. Though the exact mechanism of action remains to be fully elucidated, available knowledge supports the ability of microbiota-fermented short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, to influence epigenetic and metabolic cascades controlling gene expression, chemotaxis, differentiation, proliferation, and apoptosis in several non-immune and immune cell subsets. While used as preferred metabolic substrates and sources of energy by colonic gut epithelial cells, most recent evidence indicates that these metabolites regulate immune functions, and in particular fine-tune T cell effector, regulatory and memory phenotypes, with direct in vivo consequences on the efficacy of chemotherapy, radiotherapy and immunotherapy. Most recent data also support the use of these metabolites over the course of T cell manufacturing, paving the way for refined adoptive T cell therapy engineering. Here, we review the most recent advances in the field, highlighting in vitro and in vivo evidence for the ability of SCFAs to shape T cell phenotypes and functions.
Indomethacin-induced oxidative stress enhances death receptor 5 signaling and sensitizes tumor cells to adoptive T-cell therapy
Authors: Nada S Aboelella, Caitlin Brandle, Ogacheko Okoko, Md Yeashin Gazi, Zhi-Chun Ding, Hongyan Xu, Gregory Gorman, Roni Bollag, Marco L Davila, Locke J Bryan, David H Munn, Gary A Piazza, Gang Zhou
Journal: Journal for ImmunoTherapy of Cancer (2022)

Adoptive cell therapy (ACT) using genetically modified T cells has evolved into a promising treatment option for patients with cancer. However, even for the best-studied and clinically validated CD19-targeted chimeric antigen receptor (CAR) T-cell therapy, many patients face the challenge of lack of response or occurrence of relapse. There is increasing need to improve the efficacy of ACT so that durable, curative outcomes can be achieved in a broad patient population.Here, we investigated the impact of indomethacin (indo), a non-steroidal anti-inflammatory drug (NSAID), on the efficacy of ACT in multiple preclinical models. Mice with established B-cell lymphoma received various combinations of preconditioning chemotherapy, infusion of suboptimal dose of tumor-reactive T cells, and indo administration. Donor T cells used in the ACT models included CD4+ T cells expressing a tumor-specific T cell receptor (TCR) and T cells engineered to express CD19CAR. Mice were monitored for tumor growth and survival. The effects of indo on donor T cell phenotype and function were evaluated. The molecular mechanisms by which indo may influence the outcome of ACT were investigated.ACT coupled with indo administration led to improved tumor growth control and prolonged mouse survival. Indo did not affect the activation status and tumor infiltration of the donor T cells. Moreover, the beneficial effect of indo in ACT did not rely on its inhibitory effect on the immunosuppressive cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) axis. Instead, indo-induced oxidative stress boosted the expression of death receptor 5 (DR5) in tumor cells, rendering them susceptible to donor T cells expressing TNF-related apoptosis-inducing ligand (TRAIL). Furthermore, the ACT-potentiating effect of indo was diminished against DR5-deficient tumors, but was amplified by donor T cells engineered to overexpress TRAIL.Our results demonstrate that the pro-oxidative property of indo can be exploited to enhance death receptor signaling in cancer cells, providing rationale for combining indo with genetically modified T cells to intensify tumor cell killing through the TRAIL-DR5 axis. These findings implicate indo administration, and potentially similar use of other NSAIDs, as a readily applicable and cost-effective approach to augment the efficacy of ACT.
Adaptive Bird-Like Genome Miniaturization During the Evolution of Scallop Swimming Lifestyle
Authors: Yuli Li, Yaran Liu, Hongwei Yu, Fuyun Liu, Wentao Han, Qifan Zeng, Yuehuan Zhang, Lingling Zhang, Jingjie Hu, Zhenmin Bao, Shi Wang
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Genome miniaturization drives key evolutionary innovations of adaptive traits in vertebrates, such as the flight evolution of birds. However, whether similar evolutionary processes exist in invertebrates remains poorly understood. Derived from the second-largest animal phylum, scallops are a special group of bivalve molluscs and acquire the evolutionary novelty of the swimming lifestyle, providing excellent models for investigating the coordinated genome and lifestyle evolution. Here, we show for the first time that genome sizes of scallops exhibit a generally negative correlation with locomotion activity. To elucidate the co-evolution of genome size and swimming lifestyle, we focus on the Asian moon scallop (Amusium pleuronectes) that possesses the smallest known scallop genome while being among scallops with the highest swimming activity. Whole-genome sequencing of A. pleuronectes reveals highly conserved chromosomal macrosynteny and microsynteny, suggestive of a highly contracted but not degenerated genome. Genome reduction of A. pleuronectes is facilitated by significant inactivation of transposable elements, leading to reduced gene length, elevated expression of genes involved in energy-producing pathways, and decreased copy numbers and expression levels of biomineralization-related genes. Similar evolutionary changes of relevant pathways are also observed for bird genome reduction with flight evolution. The striking mimicry of genome miniaturization underlying the evolution of bird flight and scallop swimming unveils the potentially common, pivotal role of genome size fluctuation in the evolution of novel lifestyles in the animal kingdom.
Predicting the outcome for patients with myelofibrosis undergoing an allogeneic hemopoietic stem cell transplant
Authors: Federica Sora, Sabrina Giammarco, Anna Maria Raiola, Carmen Di Grazia, Stefania Bregante, Francesca Gualandi, Riccardo Varaldo, Patrizia Chiusolo, Simona Sica, Luca Laurenti, Idanna Innocenti, Francesco Autore, Elisabetta Metafuni, Eugenio Galli, Andrea Bacigalupo, Emanuele Angelucci
Journal: Blood Cancer Journal (2022)
Distribution of clonal hematopoiesis of indeterminate potential (CHIP) is not associated with race in patients with plasma cell neoplasms
Authors: Marie-France Gagnon, Shulan Tian, Susan Geyer, Neeraj Sharma, Celine M. Vachon, Yael Kusne, P. Leif Bergsagel, A. Keith Stewart, S. Vincent Rajkumar, Shaji Kumar, Sikander Ailawadhi, Linda B. Baughn
Journal: Blood Cancer Journal (2022)

Distribution of clonal hematopoiesis
Therapy-related myeloid neoplasms following chimeric antigen receptor T-cell therapy for Non-Hodgkin Lymphoma
Authors: Hassan B. Alkhateeb, Razan Mohty, Patricia Greipp, Radhika Bansal, Matthew Hathcock, Allison Rosenthal, Hemant Murthy, Mohamed Kharfan-Dabaja, Jose C. Bisneto Villasboas, Nora Bennani, Stephen M. Ansell, Mrinal M. Patnaik, Mark R. Litzow, Rong He, Dong Chen, Aref Al-Kali, Saad S. Kenderian, Yi Lin, Mithun Vinod Shah
Journal: Blood Cancer Journal (2022)
Reinforcement learning in ophthalmology: potential applications and challenges to implementation
Authors: Siddharth Nath, Edward Korot, Dun Jack Fu, Gongyu Zhang, Kapil Mishra, Aaron Y Lee, Pearse A Keane
Journal: The Lancet Digital Health (2022)

Reinforcement learning is a subtype of machine learning in which a virtual agent, functioning within a set of predefined rules, aims to maximise a specified outcome or reward. This agent can consider multiple variables and many parallel actions at once to optimise its reward, thereby solving complex, sequential problems. Clinical decision making requires physicians to optimise patient outcomes within a set practice framework and, thus, presents considerable opportunity for the implementation of reinforcement learning-driven solutions. We provide an overview of reinforcement learning, and focus on potential applications within ophthalmology. We also explore the challenges associated with development and implementation of reinforcement learning solutions and discuss possible approaches to address them.
CRISPR-mediated TGFBR2 knockout renders human ovarian cancer tumor-infiltrating lymphocytes resistant to TGF-β signaling
Authors: Samantha M Fix, Marie-Andrée Forget, Donastas Sakellariou-Thompson, Yunfei Wang, Tamara M Griffiths, Minjung Lee, Cara L Haymaker, Ana Lucía Dominguez, Rafet Basar, Christopher Reyes, Sanjay Kumar, Larissa A Meyer, Patrick Hwu, Chantale Bernatchez, Amir A Jazaeri
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The correlation between elevated T-cell infiltration and improved survival of ovarian cancer (OvCa) patients suggests that endogenous tumor-infiltrating lymphocytes (TIL) possess some degree of antitumor activity that can be harnessed for OvCa immunotherapy. We previously optimized a protocol for ex vivo OvCa TIL expansion for adoptive cell therapy, which is now being tested in a clinical trial at our institution ( NCT03610490 ). Building on this success, we embarked on genetic modification of OvCa TIL to overcome key immunosuppressive factors present in the tumor microenvironment. Here, we present the preclinical optimization of CRISPR/Cas9-mediated knockout of the TGF-β receptor 2 ( TGFBR2 ) in patient-derived OvCa TIL. Methods OvCa TILs were generated from four patients’ tumor samples obtained at surgical resection and subjected to CRISPR/Cas9-mediated knockout of TGFBR2 before undergoing a rapid expansion protocol. TGFBR2 -directed gRNAs were comprehensively evaluated for their TGFBR2 knockout efficiency and off-target activity. Furthermore, the impact of TGFBR2 knockout on TIL expansion, function, and downstream signaling was assayed. Results TGFBR2 knockout efficiencies ranging from 59±6% to 100%±0% were achieved using 5 gRNAs tested in four independent OvCa TIL samples. TGFBR2 knockout TIL were resistant to immunosuppressive TGF-β signaling as evidenced by a lack of SMAD phosphorylation, a lack of global transcriptional changes in response to TGF-β stimulation, equally strong secretion of proinflammatory cytokines in the presence and absence of TGF-β, and improved cytotoxicity in the presence of TGF-β. CRISPR-modification itself did not alter the ex vivo expansion efficiency, immunophenotype, nor the TCR clonal diversity of OvCa TIL. Importantly for clinical translation, comprehensive analysis of CRISPR off-target effects revealed no evidence of off-target activity for our top two TGFBR2 -targeting gRNAs. Conclusions CRISPR/Cas9-mediated gene knockout is feasible and efficient in patient-derived OvCa TIL using clinically-scalable methods. We achieved efficient and specific TGFBR2 knockout, yielding an expanded OvCa TIL product that was resistant to the immunosuppressive effects of TGF-β. This study lays the groundwork for clinical translation of CRISPR-modified TIL, providing opportunities for engineering more potent TIL therapies not only for OvCa treatment, but for the treatment of other solid cancers as well.
Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma
Authors: Maciej Daniszewski, Anne Senabouth, Helena H. Liang, Xikun Han, Grace E. Lidgerwood, Damián Hernández, Priyadharshini Sivakumaran, Jordan E. Clarke, Shiang Y. Lim, Jarmon G. Lees, Louise Rooney, Lerna Gulluyan, Emmanuelle Souzeau, Stuart L. Graham, Chia-Ling Chan, Uyen Nguyen, Nona Farbehi, Vikkitharan Gnanasambandapillai, Rachael A. McCloy, Linda Clarke, Lisa S. Kearns, David A. Mackey, Jamie E. Craig, Stuart MacGregor, Joseph E. Powell, Alice Pébay, Alex W. Hewitt
Journal: Cell Genomics (2022)

To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared with those from healthy individuals. We performed single-cell RNA sequencing of a total of 247,520 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 4,443 significant loci across all cell types, 312 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 97 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.
Review: Emerging Eye-Based Diagnostic Technologies for Traumatic Brain Injury
Authors: Georgia Harris, Jonathan James Stanley Rickard, Gibran Butt, Liam Kelleher, Richard James Blanch, Jonathan Cooper, Pola Goldberg Oppenheimer
Journal: IEEE Reviews in Biomedical Engineering (2022)

The study of ocular manifestations of neurodegenerative disorders, Oculomics, is a growing field of investigation for early diagnostics, enabling structural and chemical biomarkers to be monitored overtime to predict prognosis. Traumatic brain injury (TBI) triggers a cascade of events harmful to the brain, which can lead to neurodegeneration. TBI, termed the "silent epidemic" is becoming a leading cause of death and disability worldwide. There is currently no effective diagnostic tool for TBI, and yet, early-intervention is known to considerably shorten hospital stays, improve outcomes, fasten neurological recovery and lower mortality rates, highlighting the unmet need for techniques capable of rapid and accurate point-of-care diagnostics, implemented in the earliest stages. This review focuses on the latest advances in the main neuropathophysiological responses and the achievements and shortfalls of TBI diagnostic methods. Validated and emerging TBI-indicative biomarkers are outlined and linked to ocular neuro-disorders. Methods detecting structural and chemical ocular responses to TBI are categorised along with prospective chemical and physical sensing techniques. Particular attention is drawn to the potential of Raman spectroscopy as a non-invasive sensing of neurological molecular signatures in the ocular projections of the brain, laying the platform for the first tangible path towards alternative point-of-care diagnostic technologies for TBI.
Sublingual Gland Observed on Salivary Gland Scan
Authors: Ju-Yang Jung, Joon-Kee Yoon, Su Jin Lee, Young-Sil An
Journal: Clinical Nuclear Medicine (2022)

Abstract The major salivary glands, namely, the parotid, submandibular, and sublingual glands, are important in maintaining oral cavity health. A salivary gland scan is used to evaluate the uptake and excretory function of the salivary glands. By intravenously injecting 99m TcO 4 − , which is distributed like chloride ions in the body, the glands become visible on the salivary gland scan. The parotid and submandibular glands are typically appreciated on the salivary gland scan, but the sublingual gland is not. We present a rare image of a prominent sublingual gland on a salivary gland scan.
Correction: Cytoplasmic Irradiation Results in Mitochondrial Dysfunction and DRP1-Dependent Mitochondrial Fission
Authors: Bo Zhang, Mercy M. Davidson, Hongning Zhou, Chunxin Wang, Winsome F. Walker, Tom K. Hei
Journal: Cancer Research (2022)

In the original version of this article (1), there was an error in Fig. 6A. Specifically, the images in Fig. 6A were the same images used in Fig. 2A. This error was made during the final production phase on the manuscript. The correct images have been provided, and the error has been corrected in the latest online HTML and PDF version of the article. The authors regret this error.
In COVID-19 with hypoxemia, 12 vs. 6 mg/d of dexamethasone did not increase days alive without life support
Authors: Michael J. Jacka
Journal: Annals of Internal Medicine (2022)

Munch MW, Myatra SN, Vijayaraghavan BK, et al. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. JAMA. 2021;326:1807-17. 34673895.
Assessment of the effect of snakebite on health and socioeconomic factors using a One Health perspective in the Terai region of Nepal: a cross-sectional study
Authors: Sara Babo Martins, Isabelle Bolon, Gabriel Alcoba, Carlos Ochoa, Paul Torgerson, Sanjib K Sharma, Nicolas Ray, François Chappuis, Rafael Ruiz de Castañeda
Journal: The Lancet Global Health (2022)

BackgroundSnakebite envenoming has a substantial health and socioeconomic effect in rural communities. However, there are insufficient epidemiological and animal data, which prevents accurate assessment on the effects of snakebite. We aimed to assess the health and socioeconomic effect of snakebite using a One Health perspective.MethodsIn this cross-sectional survey-based study, we assessed the health and socioeconomic effects of snakebite data using a multicluster survey that was previously done as part of the SNAKE-BYTE project in the Terai region, Nepal. Health effect was measured in terms of disability-adjusted life years (DALYs). Livelihood losses encompassed out-of-pocket health-care expenditures, losses of productivity due to days off work, and the losses due to mortality and treatment costs in domestic animals. Mortality losses in domestic animals were also estimated as animal loss equivalents, and overall human and animal health effect expressed using modified DALYs for zoonotic disease (zDALYs).FindingsWe estimate an annual snakebite burden of 200 799 DALYs (95% CI 103 137–357 805), mostly due to mortality in children and women. Snakebite is estimated to lead to US$2·8 million in yearly livelihood losses associated with human and animal cases. Overall, we estimate a yearly human and animal health burden of 202 595 zDALYs (104 300–360 284).InterpretationThese findings present robust evidence on the extent of snakebite's health and socioeconomic effect and emphasise the need for a One Health perspective. The results also stress how improved data collection at the community level is crucial for improved assessments of its effect.FundingSwiss National Science Foundation.
Snakebite epidemiology in humans and domestic animals across the Terai region in Nepal: a multicluster random survey
Authors: Gabriel Alcoba, Sanjib Kumar Sharma, Isabelle Bolon, Carlos Ochoa, Sara Babo Martins, Manish Subedi, Bhupendra Shah, Anup Ghimire, Etienne Gignoux, Francisco Luquero, Rafael Ruiz de Castañeda, Nicolas Ray, François Chappuis
Journal: The Lancet Global Health (2022)

BackgroundEach year, 2 million people worldwide are bitten by snakes, resulting in an estimated 81 000–138 000 deaths. WHO has added snakebite envenoming to the list of neglected tropical diseases, highlighting the need for stronger epidemiological evidence in endemic countries, such as Nepal.MethodsWe conducted a cross-sectional survey in villages randomly geospatially selected from aerial images from across the Nepal's Terai lowlands region (excluding towns and cities). We collected data between Nov 30, 2018 and May 7, 2019, and analysed snakebite incidence rates and outcomes in humans and domestic animals.FindingsAmong 63 454 human participants living in 13 879 households (249 villages), 166 were bitten by a snake over the previous 12 months; 48·8% were envenomed and 7·8% died. This corresponded to an annual crude incidence rate of 262 snakebites (adjusted incidence of 251·1 [95% CI 201·7–312·6]) and 20 deaths (22·4 [11·9–42·1]) per 100 000 people, extrapolating to 26 749–37 661 yearly bitten people and 2386–3225 deaths. Bitten people had a median age of 30 years (IQR 20–45) and with available data, 64% were female. Children younger than 15 years (n=6; 46%) and females (n=10; 77%) were disproportionately affected among the 13 people who died. The incidence was higher in the Eastern region, and mortality was higher in the Central region. Of 183 949 animals, owners reported 144 snakebites, with an annual incidence rate of 42–202 per 100 000 and mortality of 79–100%, varying by animal type. Spatial and seasonal incidence were similar in humans and in animals.InterpretationThis study provides the first epidemiological estimates of snakebite envenoming in humans and domestic animals across Nepal's Terai lowlands. It was also the first to use a community-based, transdisciplinary, and One Health design. These findings call for a strengthening of preventive measures and better access to life-saving treatments.FundingSwiss National Science Foundation project 315130_176271 (SNAKE-BYTE).